Process for preparing chiral octenoic acid derivatives

ABSTRACT

The invention relates to a process for preparing chiral octenoic acid derivatives, which constitute important intermediates in the preparation of medicament active ingredients, and also to novel intermediates which are used in the process for preparing the octenoic acid derivatives mentioned.

The invention relates to a process for preparing chiral octenoic acidderivatives which constitute important intermediates in the preparationof medicament active ingredients. The invention also relates to novelintermediates which are used in the process for preparing the octenoicacid derivatives mentioned.

BACKGROUND OF THE INVENTION

Documents WO 02/02508, WO 02/08172 and WO 01/09083 describe chiraloctenoic acid derivatives of the general formula (I) as importantintermediates especially in the multistage preparation of the renininhibitor known as “aliskiren” (CAN: 173334-57-1) from Novartis.According to these documents, the chiral phenyl-substituted octenoicacid derivatives are formed from two chiral blocks, one unit being achiral 3-phenyl-2-isopropylpropyl halide (known from WO 02/02487 and WO02/02500) and the other unit being a chiral5-halo-2-isopropylpent-4-enoic acid (described in WO 01/09079 and WO02/092828), which are combined to give the desired product. The twochiral blocks are prepared separately via complex multistage syntheses,as described in the abovementioned documents. The overall preparationprocess for the chiral phenyl-substituted octenoic acid derivatives ofthe general formula (I) is thus very complex, and additionally includesan asymmetric hydrogenation step in which a very expensive homogeneouschiral Rh catalyst which is not readily available is needed, which makesthe process very costly overall.

BRIEF SUMMARY OF THE INVENTION

It was thus an object of the present invention to provide a simplifiedpreparation process for octenoic acid derivatives of the general formula(I).

The object stated is achieved by a process for preparing compounds ofthe general formula (I)

-   -   in which        -   R¹ and R² are each independently hydroxyl, alkoxy, aryloxy,            arylalkyloxy or alkoxyalkoxy;        -   R³ is a heterocarbon group containing at least one            heteroatom selected from O and N with at least one            carbon-heteroatom multiple bond at the C-1 position, such as            COOR⁶            -   in which R⁶ is hydrogen, alkyl, aryl, arylalkyl or                trialkylsilyl;        -   nitrile;        -   C(O)R⁷,            -   in which R⁷ is hydrogen, halogen, O⁻, OM,                -   in which M is an alkali metal or an equivalent of an                    alkaline earth metal,            -   OCOR¹²,                -   in which R¹² is branched lower alkyl having from 1                    to 5 carbon atoms, preferably pivaloyl,            -   OCOCF₃, OSO₂CH₃ or OSO₂CF₃        -   or is a protecting or activating group such as            C(O)N-alkyl-O-alkyl or C(O)NR⁴R⁵,            -   in which R⁴ and R⁵ are each independently hydrogen,                alkyl, aryl, arylalkyl, trialkylsilyl or the like, or R⁴                and R⁵ together with the nitrogen form a five- to                six-membered heterocyclic ring system which may                optionally have from 1 to 3 additional heteroatoms;        -   or salts thereof,    -   wherein a compound of the general formula (II)

-   -   -   in which        -   R³ is in each case independently as defined above under the            formula (I);

    -   is reacted in an addition reaction with a compound of the        formula (III)

-   -   -   in which        -   Y is halogen, metal, metal halide, metal alkoxide or metal            carboxylate,        -   R¹ and R² are each as defined above under the formula (I),        -   or        -   Y is hydrogen, and        -   R¹ is a protected hydroxyl function, such as a            trifluoromethanesulfonate or trifluoroacetate group;        -   R² is as defined above under the formula (I),

    -   to obtain a compound of the formula (IV)

-   -   -   in which        -   R¹, R² and R³ are each as defined above under the formula            (I);        -   the dotted line represents a single or double bond;        -   R⁵ is O or NR⁸ in which R⁸ is hydrogen or alkyl if the            dotted line represents a double bond, or        -   R⁵ is OH or NR⁸R⁹ in which R⁸ and R⁹ are each independently            hydrogen or alkyl if the dotted line represents a single            bond;

    -   and the compound of the formula (IV) is subjected to at least        one reduction reaction to obtain the desired product of the        formula (I);

    -   or

    -   the compound of the general formula (II) is subjected to at        least one reduction reaction to obtain the compound of the        formula (V)

-   -   -   in which        -   R³ is as defined above under formula (I);        -   Z is a leaving group, such as halogen, mesyl, tosyl or            triflate;

    -   and the compound of the formula (IV) is reacted in an addition        reaction with a compound of the formula (III) to obtain the        desired product of the formula (I).

In a preferred embodiment of the process according to the invention, thecompound of the formula (II) is used as a mixture of the stereoisomers.

The process according to the invention preferably comprises an isomerseparation step before or after one of the addition or reduction steps.The isomers can be separated in a manner known per se, for example byvarious crystallization techniques, chromatography, etc., in one or moresteps. In a further preferred embodiment, the process according to theinvention comprises, as well as the isomer separation step mentioned,additionally an isomerization or racemization of the undesired isomers.

Advantageously, the radicals in the formula (I) are defined as follows:

-   -   R¹: hydroxyl or branched or unbranched lower alkoxy having from        1 to 5 carbon atoms, such as methoxy, ethoxy, n- and i-propoxy,        n-, i- and t-butoxy or pentoxy, aryloxy such as phenyloxy,        naphthyloxy or derivatives thereof, or benzyloxy or branched or        unbranched alkoxyalkoxy having in each case from 1 to 5,        preferably from 1 to 2 carbon atoms in the alkoxy group, such as        1-methoxymethoxy, 1-methoxy-2-ethoxy, 1-methoxy-3-propoxy,        1-methoxy-4-butoxy, etc., more particularly 1-methoxymethoxy,        1-methoxy-2-ethoxy, 1-methoxy-3-propoxy, 1-methoxy-4-butoxy,        especially 1-methoxy-3-propoxy,    -   R²: hydroxyl or branched or unbranched lower alkoxy having from        1 to 5 carbon atoms, such as methoxy, ethoxy, n- and i-propoxy,        n-, i- and t-butoxy or pentoxy, aryloxy such as phenyloxy,        naphthyloxy or derivatives thereof, or benzyloxy or branched or        unbranched alkoxyalkoxy having in each case from 1 to 5,        preferably from 1 to 2 carbon atoms in the alkoxy group, such as        1-methoxymethoxy, 1-methoxy-2-ethoxy, 1-methoxy-3-propoxy,        1-methoxy-4-butoxy, etc., more preferably methoxy,        and    -   R³: COOR⁶ in which R⁶ is hydrogen, branched or unbranched lower        alkyl having from 1 to 5 carbon atoms, aryl, benzyl or        trialkylsilyl, nitrile, C(O)R⁷ in which R⁷ is halogen, OM in        which M is an alkali metal or an equivalent of an alkaline earth        metal, or C(O)NR⁴R⁵ in which R⁴ and R⁵ are each independently        branched or unbranched lower alkyl having from 1 to 5 carbon        atoms, or benzyl.

The process according to the invention more preferably serves to preparethe compound of the formula (VI)

-   -   in which R¹, R² and R³ are each as defined above under formula        (I).

In particular, the process according to the invention serves to preparethe compound of the formula (VII)

-   -   in which    -   MOPO is methoxypropoxy and R⁶ is as defined above under formula        (I).

In a further preferred variant of the process according to theinvention, R³ is independently carboxyl or nitrite.

The addition reaction is preferably carried out with a compound of theformula (III) in which Y represents various metals, such as alkalimetals, or metal halide or metal alkoxide or metal carboxylate, in whichthe metal may be Mg, Al, B, Mn, Cu, Cd, Zn and Sn. More preferably, Y isLi, Na, CuCl, CuBr, CuI, MgCl or MgBr.

The reduction is carried out in one or two steps, for example with metalhydrides or trialkylsilane in the presence of acids or with Lewis acids.

In a further preferred embodiment of the process according to theinvention, the compound of the formula (VII) is converted in anadditional amidation in a known manner to the compound of the formula(VIII)

If the addition is carried out with a compound of the formula (III) inwhich Y is hydrogen and R¹ is a protected hydroxyl function and R² is asdefined above under formula (I), the process according to the inventionpreferably comprises a further alkylation step for converting R¹ toalkoxy or alkoxyalkoxy.

The invention further relates to compounds of the formula (IIa)

-   -   in which    -   R¹⁰ is a heterocarbon group containing at least one heteroatom        selected from O and N with at least one carbon-heteroatom        multiple bond at the C-1 position, such as        -   COOR⁶ in which R⁶ is hydrogen, alkyl, aryl, arylalkyl or            trialkylsilyl;        -   nitrile;        -   C(O)R⁷,            -   in which R⁷ is hydrogen, halogen, O⁻, OM,                -   in which M is an alkali metal or an equivalent of an                    alkaline earth metal,            -   OCOR¹²,                -   in which R¹² is branched lower alkyl having from 1                    to 5 carbon atoms, preferably pivaloyl, or            -   OCOCF₃, OSO₂CH₃ or OSO₂CF₃        -   or is a protecting or activating group such as            C(O)N-alkyl-O-alkyl or C(O)NR⁴R⁵,            -   in which R⁴ and R⁵ are each independently hydrogen,                alkyl, aryl, arylalkyl, trialkylsilyl or the like, or R⁴                and R⁵ together with the nitrogen atom form a five- to                six-membered heterocyclic ring system which may                optionally have from 1 to 3 additional heteroatoms;                -   where R⁴ and R⁵ together with the nitrogen cannot be                    a 4(S)-substituted oxazolidin-2-on-3-yl in each R¹⁰                    if both radicals are C(O)NR⁴R⁵,                    or salts thereof.

A preferred group of the compounds according to the invention of theformula (IIa) is that of (S,S)-enantiomers of the formula (IIb)

In a further preferred group of compounds according to the invention ofthe formula (IIa) or (IIb), R¹⁰ is C(O)R⁷ in which R⁷ is hydrogen,halogen, O⁻, OM in which M is an alkali metal, an equivalent of analkaline earth metal, OCOR¹² in which R¹² is branched lower alkyl havingfrom 1 to 5 carbon atoms, preferably pivaloyl, or OCOCF₃, OSO₂CH₃ orOSO₂CF₃, nitrile or COOR⁶ in which R⁶ is as defined above under formula(I), and is preferably hydrogen.

More preferably, R¹⁰ is in each case independently nitrile or COCl orCOBr or COOR⁶ in which R⁶ is as defined above under formula (I), and ispreferably hydrogen.

The invention further relates to compounds of the formula (IV)

-   -   in which    -   R¹, R² and R³ are each as defined above under the formula (I);    -   the dotted line represents a single or double bond;    -   R⁵ is O or NR⁸ in which R⁸ is hydrogen or alkyl if the dotted        line represents a double bond, or    -   R⁵ is OH or NH₂ if the dotted line represents a single bond,        or salts thereof, preferably the (S,S)-enantiomers. In the        context of the present invention, the preferred        (S,S)-enantiomers are understood to mean compounds in which the        isopropyl groups of the octane side chains have the following        configuration:

The (S,S)-enantiomers mentioned can advantageously be converted tocompounds of the formula (I) with retention of the two chiral centers.

In the context of the present invention, the expression “halogen”relates to chlorine, bromine, iodine.

“Alkyl” relates, unless stated otherwise, to straight-chain or branchedor cyclic saturated hydrocarbons or combinations thereof with preferablyfrom 1 to 20 carbon atoms, especially from 1 to 10 carbon atoms, morepreferably from 1 to 5 carbon atoms. Examples of such alkyl groups(provided that the designated length includes the specific example) aremethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

“Alkoxy” relates to straight-chain or branched saturated alkyl which isbonded via oxygen and has preferably from 1 to 20 carbon atoms,especially from 1 to 10 carbon atoms, more preferably from 1 to 5 carbonatoms, most preferably from 1 to 2 carbon atoms. Examples of such alkoxygroups (provided that the designated length includes the specificexample) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy andtert-butoxy.

The alkyl and alkoxy groups may be substituted by one or more of thefollowing groups selected from halogen, hydroxyl, cyano, C₁-C₆-alkoxy,nitro, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, carboxyl,C₁-C₆-alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl,trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl,pentahaloethyl.

The term “cycloalkyl” represents, unless stated otherwise, an organicradical which is derived from a monocyclic (C₃-C₇)-cycloalkyl compoundby removal of one hydrogen radical from one ring carbon atom of thecycloalkyl compound. Examples of cycloalkyl groups are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,1,3-cyclobutadienyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl,1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl,bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane. The term “cycloalkyl”also encompasses cycloalkenyl groups having one or two double bonds.

The expression “heterocyclic” denotes a monocyclic, heterocyclic ringsystem. Monocyclic heterocyclic rings consist of from about 3 to 7 ringatoms with from 1 to 5 heteroatoms selected from N, O and S, andpreferably from 3 to 7 atoms in the ring. Bicyclic heterocycles consistof from about 5 to 17 ring atoms, preferably from 5 to 12 ring atoms.

The expression “aryl” denotes a cyclic or polycyclic ring consisting offrom 6 to 12 carbon atoms, which may be unsubstituted or is substitutedby one or more substituent groups which are specified above for thealkyl and alkoxy groups. Examples of aryl groups are phenyl,2,6-dichlorophenyl, 3-methoxyphenyl, naphthyl, 4-thionaphthyl,tetralinyl, anthracenyl, phenanthrenyl, benzonaphthenyl, fluorenyl,2-acetamidofluoren-9-yl and 4′-bromobiphenyl.

The expression “heteroaryl” denotes an aromatic cyclic or polycyclicring system having from 1 to 9 carbon atoms and from 1 to 4 heteroatomsselected from N, O and S. Typical heteroaryl groups are 2- or 3-thienyl,2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4- or5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, tetrazolyl,2-, 3- or 4-pyridinyl, 3-, 4- or 5-pyridazinyl, 2-pyrazinyl, 2-, 4- or5-pyrimidinyl. The heteroaryl groups may be unsubstituted or substitutedby from 1 of 3 of the substituents as specified above for the alkyl andalkoxy groups, for example cyanothienyl and formylpyrrolyl.

The expression “heterocarbon group” denotes a group containing at leastone heteroatom selected from O and N with at least one carbon-heteroatommultiple bond at the C-1 position, the group being bonded via the C-1atom. The group is essentially a functionality which can be bonded to anaromatic system via an addition or can be reduced with addition of aleaving group onto the C-1 atom. Typical heterocarbon groups arecarboxylic acid groups and derivatives thereof, such as acid halides,amides and esters, and also nitrites.

The expression “salts” relates preferably to metal salts, especiallyalkali metal salts.

Hydrates and solvates of the compounds according to the invention arelikewise included.

The compounds according to the invention of the formula (IIa) and (IV)and the compounds of the formula (I) possess chiral centers and may bepresent in any stereoisomeric form. The present invention encompassesall stereoisomeric forms, or mixtures thereof, of a compound accordingto the invention or desired compound, it being known how the opticallyactive forms can be obtained (for example by separating the racemic formby recrystallization methods, by synthesis from optically activestarting materials, by chiral synthesis or by chromatographic separationby means of a chiral stationary phase).

The compounds according to the invention of the formulae (IIa), (IIb)and (IV) can advantageously be used to prepare octenoic acidderivatives, more preferably in the process according to the invention.

The process according to the invention is based essentially on theseparate preparation first of the side chain of the compound of thegeneral formula (I) which contains two chiral centers, taking account ofthe symmetry element present therein, which significantly simplifies theoverall synthesis and can considerably reduce the number of reactionsteps. In a second stage, this symmetrical chiral side chain precursorcan be coupled to a suitable aromatic unit to obtain the desired chiraloctenoic acid of the formula (I) within few reaction steps.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of Scheme 1 showing synthesis route A) firstaddition of the compound of the formula (III) to obtain a compound ofthe formula (IV) and subsequent reduction of the compound of the formula(IV).

FIG. 2 is an illustration of Scheme 1a showing the intermediate offormula (IV) being obtained by addition of a compound of formula (III)onto a chiral compound of formula (IIe) which leads to the compound offormula (I).

FIG. 3 is an illustration of Scheme 2 showing the intermediate offormula (IV) being obtained by addition of a compound of formula (III)on a chiral compound of formula (IIf) which leads to the compound offormula (I). Also, showing the compound of formula (I) being obtaineddirectly by a coupling reaction of the chiral compound of formula (Va)with a compound of formula (III).

FIG. 4 is an illustration of Scheme 3 showing the preparation of thecompound of formula (I) via nitrile compounds of formula (IV).

FIG. 5 is an illustration of Scheme 4 showing the compound of formula(I) being obtained by alkylating the phenolic group of a compound offormula (Ia) in the presence of a base, wherein formula (Ia) wasprepared according to Scheme 3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention and additional embodiments of the invention aredescribed in detail hereinafter in the detailed description.

According to the invention, the compound of the general formula (I) canbe obtained proceeding from a compound of the general formula (II) bytwo alternative routes, i.e.

A) either by a first addition of the compound of the formula (III) toobtain a compound of the formula (IV) and subsequent reduction of thecompound of the formula (IV) or

B) by reduction of the compound of the formula (II) to obtain a compound(V) and subsequent addition of the compound of the formula (III).

In scheme 1, synthesis route A) is illustrated in detail hereinafterwith reference to the preferred embodiment with an additional isomerseparation, which affords the desired product of the formula (I) inisomerically pure form. Proceeding from a compound of the formula (II),addition of a compound of the formula (IIIa) leads to an 8-oxooctenoicacid (IV) which has, in the 1 position, i.e. in the benzyl position, theR⁵ radical bonded via a single or double bond. In the present case, R⁵is, by way of example, a keto group which is reduced in one or moresteps in the subsequent reaction. R⁵ might equally be a likewisereducible hydroxyl group. As shown, the intermediate of the formula (IV)can be obtained by two alternative routes. For instance, proceeding froma mixture of the stereoisomers of the compound of the formula (II),either first an isomer separation and then the addition of the compoundof the formula (IIIa) or first the addition and then an enantiomerseparation can be undertaken. It is obvious that the reaction can alsobe carried out with different isomers than those specified of thecompounds of the formulae (II) and (IV) or mixtures thereof, which leadsto corresponding isomers and/or mixtures of the compound of the formula(I).

Preferably, R¹ and R² are each independently hydroxyl or branched orunbranched lower alkoxy having from 1 to five carbon atoms, such asmethoxy, ethoxy, n- and i-propoxy, n-, i- and t-butoxy or pentoxy,aryloxy such as phenyloxy, naphthyloxy or derivatives thereof, orbenzyloxy or branched or unbranched alkoxyalkoxy having in each casefrom 1 to 5, preferably from 1 to 2 carbon atoms in the alkoxy group,such as 1-methoxymethoxy, 1-methoxy-2-ethoxy, 1-methoxy-3-propoxy,1-methoxy-4-butoxy, etc.

The X radical is appropriately O⁻, OH or a salt, such as OM in which Mis an alkali metal or an equivalent of an alkaline earth metal. Furthersuitable meanings of X are OR¹¹ in which R¹¹ is alkyl, preferablyunbranched or branched lower alkyl having from 1 to 5 carbon atoms, arylsuch as phenyl, naphthyl or alkoxy derivatives thereof, benzyl,diphenylmethyl, trityl or trialkylsilyl or NR⁴R⁵ in which R⁴ and R⁵ areeach independently alkyl, preferably unbranched or branched lower alkylhaving from 1 to 5 carbon atoms, or benzyl or trialkylsilyl. R⁴ and R⁵may, together with the nitrogen, form a typically 5- to 6-memberedheterocyclic ring system such as pyrrole, imidazole and the like. X maylikewise be a protecting or activating group customary for carboxylicacids, such as Weinreb amide, preferably N-alkyl-O-alkyl, in which alkylis preferably straight-chain or branched lower alkyl having from 1 to 5carbon atoms, or the nitrogen is part of a heterocyclic ring system suchas pyrrole, imidazole and the like.

The reduction stage of the keto function can be carried out in one ormore steps. The reductive removal of the oxygen function in the benzylposition to the corresponding hydrocarbon can be effected via variousknown methods which do not simultaneously reduce the double bond presentin the aliphatic chain (see. J. March, John Wiley & Sons, NY, 1992,Advanced Organic Chemistry, p. 1209-1211). In the suitable methods, thereaction can be carried out without solvent, or in polar or nonpolar,protic or aprotic solvents, preferably in aprotic solvents such aschlorinated hydrocarbons or hydrocarbons, preferably at temperaturesbetween −20° C. and reflux temperature of the solvent.

Preferably, trialkylsilane can be used in the presence of acids,preferably trifluoromethanesulfonic acid or trifluoroacetic acid, orLewis acids, preferably BF₃.etherate, ZnCl₂, AlCl₃, TiCl₄.

The reduction can also be carried out in several steps when the 8-oxogroup of the compound of the formula (IV) is first reduced with, forexample, metal hydrides to give the corresponding 8-hydroxy compoundwhich, in turn, thereafter, is either reduced directly to the desiredcompound of the formula (I) or, after preceding conversion of thehydroxyl group to a suitable leaving group, preferably mesylate,tosylate, etc., and subsequent reduction, is converted to the desiredcompound of the formula (I).

Schemes 1a and 2 show further advantageous embodiments of the processaccording to the invention. The intermediate of the formula (IV) inwhich the R¹, R² and X radicals are each as defined above can beobtained by addition of a compound of the formula (III)

-   -   in which R¹ and R² are each as defined for the compound of the        formula (IV), and Y is various metals such as alkali metals or        metal halide, metal alkoxide or metal carboxylate, in which the        metal may be Mg, Al, B, Mn, Cu, Cd, Zn and Sn, onto        a) a chiral compound of the formula (IIe)

-   -   in which    -   W is in each case independently, appropriately, O⁻, OH or a salt        such as OM in which M is an alkali metal or an equivalent of an        alkaline earth metal, or is halogen, such as Cl, Br, I,        preferably Cl, or    -   is OCOR¹² in which R¹² is branched lower alkyl having from 1 to        5 carbon atoms, preferably pivaloyl, or    -   OCOCF₃, OSO₂CH₃ or OSO₂CF₃ or    -   is OR¹¹ in which R¹¹ is preferably unbranched or branched lower        alkyl having from 1 to 5 carbon atoms, aryl, benzyl or        trialkylsilyl, or NR⁴R⁵ in which R⁴ and R⁵ are each        independently preferably unbranched or branched lower alkyl        having from 1 to 5 carbon atoms or benzyl or trialkylsilyl, or        R⁴ and R⁵ may, together with the nitrogen, form a typically 5-        to 6-membered heterocyclic ring system such as pyrrole,        imidazole and the like,    -   W may likewise be a protecting or activating group customary for        carboxylic acids, such as Weinreb amide, preferably        N-alkyl-O-alkyl, in which alkyl is preferably unbranched or        branched lower alkyl having from 1 to 5 carbon atoms, or the        nitrogen is part of a heterocyclic ring system such as pyrrole,        imidazole and the like,        or        b) onto a chiral compound of the formula (IIf)

-   -   in which    -   W is advantageously hydrogen or halogen, such as Cl, Br, I,        preferably Cl, or is OCOR¹² in which R¹² is branched lower alkyl        having from 1 to 5 carbon atoms, preferably pivaloyl, or    -   OCOCF₃, OSO₂CH₃ or OSO₂CF₃ or    -   is a protecting or activating group customary for carboxylic        acids, such as Weinreb amide, preferably N-alkyl-O-alkyl, in        which alkyl is preferably unbranched or branched lower alkyl        having from 1 to 5 carbon atoms, or the nitrogen is part of a        heterocyclic ring system, such as pyrrole, imidazole and the        like, and    -   R¹³ is branched or unbranched lower alkyl having from 1 to 5        carbon atoms, or is benzyl or trialkylsilyl,        followed by a subsequent manipulation of the functional group        depending on the definition of the X radical of the compound of        the formula (IV). It is obvious that the reaction can also be        carried out with isomers other than those specified above of the        compounds of the formulae (IIe), (IIf) and (IV) or mixtures        thereof, which leads to corresponding isomers and/or mixtures of        the compound of the formula (I).

The precursor of the organometallic compound of the formula (III),preferably 4-bromo-2-(3-methoxypropyl-1-oxy)-1-methoxybenzene, can beprepared either by the process as described in documents EP 678503, WO03/103653 or WO 04/089915, or alternatively via a process in whichguaiacol is acylated, preferably benzoylated, and subsequentlybrominated (see Synthesis (5), 559, 1997 or THL 41(6), 811, 2000). Afterremoval of the protective acyl group, preferably benzyl group, the freephenol is treated with 3-halopropanol, preferably with 3-chloropropanol,and then the free hydroxyl group in the side chain is methylated withMeI or dimethyl sulfate in the presence of a base, preferably an alkalimetal hydride, alkali metal amide or tert-aliphatic amine, such astriethylamine and the like.

The organometallic reagent of the formula (III) can be prepared from theabovementioned aromatic halide, preferably bromide, either by directmetallation with metals such as alkali metals or Mg, Al, B, Mn, Zn, Sn,Cd or Cu, or via transmetallation of an initially formed alkali metalcompound in which Y is preferably Li, by addition of another metalhalide, preferably magnesium halide, (see EP 678503).

Preference is given to using a Grignard reagent of the formula (III) inwhich Y is MgCl or MgBr, which is obtained from the correspondingaromatic bromide by metallation with BuLi and subsequenttransmetallation with Mg(II) bromide or Mg(II) chloride, for example inTHF.

A compound of the formula (III) in which Y is MgCl*LiCl is obtainable,for example, by reacting the aromatic halide (III with Y=halogen),preferably the bromide, with an ^(i)PrMgCl*LiCl complex, as described byKnochel et al. in EP 1582523 A1 or in Angew. Chem. Int. Ed. 2004, 43,3333-3336.

The organometallic compound of the formula (III) is then reacted inaprotic solvent with the compound of the formula (IIe) in which W is OHor OM (acid or salts thereof, OR (ester), OCOR¹² or halogen. Preferenceis given to using the acid chloride or bromide for the reaction with thecompound of the formula (III) in the absence or in the presence ofcatalytic or stoichiometric amounts of Cu(I) or Cu(II) salts, such asCu(I) bromide or Cu(I) chloride.

The reaction temperature may be between −78° C. and reflux temperatureof the solvent; preference is given to THF at 0° C. or RT. The selectionof the aprotic solvent is uncritical. The ratio of the compounds of theformula (III) to (IIe) may be between 0.1 and 2.0, preferably between0.3 and the stoichiometric ratio.

In the case of use of the compound of the formula (IIf) in which W ishydrogen or halogen, preferably Cl or Br, a higher yield can beachieved, since the aldehyde or acid chloride leads selectively to themonoaddition product of the compound of the formula (IV).

As likewise shown in scheme 2, a compound of the formula (I) in which R¹and R² are each independently hydroxyl, unbranched or branched loweralkoxy having from 1 to 5 carbon atoms, aryloxy, arylalkyloxy orbenzyloxy, and R³ is COOR¹³, and R¹³ is branched or unbranched loweralkyl having from 1 to 5 carbon atoms or is benzyl or trialkylsilyl, canbe obtained directly by a coupling reaction of the chiral compound ofthe formula (Va)

-   -   in which    -   Z is halogen, preferably iodine, or another customary leaving        group, such as mesylate, tosylate or triflate, and    -   R¹³ is branched or unbranched lower alkyl having from 1 to 5        carbon atoms, or is benzyl or trialkylsilyl,        with a compound of the formula (III)

-   -   in which R¹ and R² are each as defined above for the compound of        the formula (I) and Y represents various metals such as alkali        metals or metal halides, in which the metal may be Mg, Al, B,        Mn, Cu and Zn.

The coupling of the compounds of the formula (III) and (Va) canpreferably be catalyzed by transition metals such as various Pd(0)complexes or Pd(II) salts, for example PdCl₂.acetonitrile complex,Pd(II) acetate, Pd(PPh₃)₄ or Pd(dba), etc., in protic or aprotic polarsolvents at a reaction temperature of from RT to reflux temperature ofthe solvent. The chiral compound of the formula (Va) can be obtainedeasily from the chiral compound of the formula (IIf) by selectivereduction of the free carboxylic acid with, for example, diborane andthe like.

EP 0678514 and U.S. Pat. No. 5,606,078 describe the stereoselectivealkylation of chiral isovaleramides with Evans auxiliaries to obtaintrans-1,8-bis[4(S)-benzyl-2-oxo-oxazolidin-3-yl]-2(S)-7(S)-diisopropyloct-4-ene-1,8-dione.However, object of the present invention is specifically the avoidanceof use of expensive chiral auxiliaries which, coupled to isovalericacid, would probably lead to stereoselective chiral precursors forpreparing compounds of the formula (IIe). The compounds of the formula(II), especially of the formula (IIe) and (IIf), in which W is asdefined above, are accordingly novel intermediates. According to theinvention, the compound of the formula (II) can be used as an easilyobtainable stereoisomeric mixture which is then subjected to anenantiomer separation if required.

As shown in scheme 1a, the chiral compound of the formula (IIe)

-   -   in which    -   W is as defined above,    -   can be obtained by the following steps:        a) alkylation of the deprotonated isovaleric acid of the formula        (X)

-   -   in which    -   Z is OH or OM in which M is an alkali metal, an equivalent of an        alkaline earth metal or —O⁻, or is OR¹¹ in which R¹¹ is        preferably unbranched or branched lower alkyl having from 1 to 5        carbon atoms, aryl, benzyl or trialkylsilyl, or NR⁴R⁵ in which        R⁴ and R⁵ are each independently unbranched or branched lower        alkyl having from 1 to 5 carbon atoms, or benzyl or        trialkylsilyl,        with a compound of the formula (XI)

-   -   in which    -   L is a customary leaving group, such as halogen, preferably Cl        or Br, or mesylate, tosylate or triflate,        b) optional hydrolysis of the ester or amide group if the ester        or the amide of isovaleric acid has been used in the alkylation        step a),        c) separation of the resulting diastereomeric acids of the        formula (IIe) and subsequent enantiomer separation (resolution)        of the racemic acid of the formula (IIe), including        epimerization of the undesired isomer,        d) conversion of the chiral acid of the formula (IIe) to the        corresponding acid chloride, ester, amide and the like depending        on the W radical by known standard methods.

The compound of the formula (IIe) may also be present as anotherenantiomer or racemate, or in meso form.

The alkylation of isovaleric acid or derivatives thereof, such as estersor amides, can be carried out in aprotic solvents, preferably THF,toluene or ether, after an initial deprotonation of the compound (X)with a strong base, such as alkali metal hydrides or alkali metalamides, preferably lithium dialkylamides such as LDA or LHMDS, at from−78° C. to 0° C. or even at RT. The deprotonated compound (X) is thentreated with 0.5 equivalent of the compound of the formula (XI) at from−78° C. to RT, preferably at 0° C. The untreated mixture comprises anessentially equimolar mixture of the two possible diastereomers, which,in the case of use of the ester or amide, is hydrolyzed to the free acid(IIe).

Alternatively, instead of the isovaleric acid derivatives, thecorresponding isopropyl malonate or the isopropyl derivative ofMeldrum's acid can be used. In this case, not only strong bases need beused, which also allows customary phase transfer catalysts or organicamides to be used for the alkylation of the compound (XI). Preference isgiven to using metal hydrides or amides, especially NaH, as the base inaprotic solvents, such as THF, toluene or ethers, which leads toparticularly high yields. After the alkylation, the malonates arehydrolyzed, followed by a decarboxylation to obtain a mixture ofdiastereomeric acids of the formula (IIe) in which W is OH or OM inwhich M is an alkali metal or the equivalent of an alkaline earth metalor —O⁻.

The removal of the desired isomer from the mixture of the diastereomericdiacid (IIe), which is to be undertaken if appropriate, can be effectedin a one-stage or two-stage process using different separationtechniques, such as chromatography or crystallization processes. Themeso acids and racemic acids are preferably first separated by means ofa kinetically controlled crystallization from a supersaturated solutionin an organic solvent or a solvent mixture, preferably ester, e.g.isopropyl acetate. In a second step, the desired enantiomer is separatedby enantiomer separation of the racemic diacid (IIe) via adiastereomeric salt with various chiral amines or complexing agents,preferably amino acids or derivatives thereof, especiallyphenylalaminol, or arylalkylamines such as 1-naphthylethylamine orphenylethylamine derivatives, preferably 1-(4-methylphenyl)ethylamine orephedrine or alkaloids such as cinchonine or other chiral amines such as3-aminopentanenitrile or 1,2-diaminocyclohexane or 2-amino-1-butanol or(1R,2S)-1-amino-2-indanol or benzylaminobutanol. The diastereomericallyenriched crystals or mother solutions can be purified byrecrystallization to obtain the pure diastereomeric salt, from which theenantiomerically pure diacid (IIe) is obtained. This salt splitting canbe carried out using standard methods, such as extraction from an acidicaqueous solution with an organic solvent, preferably esters or ethers,such as tert-butyl methyl ether, or using ion exchange resins. Theundesired isomer or mixtures thereof can be isomerized and recycled intothe separation process. The isomerization can be effected by heating thecompound (IIe) or derivatives thereof, preferably esters, acid chloridesor acid anhydrides, under basic or acidic conditions. For example, theepimerization of the meso-diacid (IIe) can be carried out under refluxin acetic anhydride in the presence of potassium acetate, which leads toa 1:1 mixture of the meso-diacid and racemic diacid (IIe).

The chiral compound of the formula (IIf)

-   -   in which    -   W and R¹³ are each as defined above,        can be obtained easily from the chiral compound (IIe) in which W        is OH by the following steps:        a1) selective monoesterification, as described in J. Chem. Soc.,        Perkin Trans 1, 1999, p. 3023-27, to obtain the monoester,        or        a2) selective hydrolysis of one of the two ester functions of a        diester compound (compound IIf with W═OR¹³)—which is itself        obtainable easily by acidic esterification from the diacid        (compound IIe with W═OH) or by reacting the acid chloride (IIe        with W═Cl) with an alcohol—under basic conditions, for example        with alkali metal or alkaline earth metal hydroxides, preferably        NaOH, KOH or Ba(OH)₂ (see Organic Syntheses, Coll. Vol. 4, p.        635 (1963); Vol. 38, p. 55 (1958); and J. Med. Chem. 2004, 47,        2318-2325) to obtain the monoester;        and further reaction of the resulting monoester, as follows:        b1) conversion of the free carboxyl function to the acid        chloride or bromide by means of thionyl chloride or bromide or        oxalyl chloride or bromide,        or        b2) conversion of the free carboxyl function to the mixed        anhydride by means of the corresponding acid chloride or        anhydride, trifluoromethanesulfonic anhydride, trifluoroacetic        anhydride or mesyl chloride,        or        b3) conversion of the free carboxyl function to aldehyde by        reduction with diborane or by hydrogenation of the acid        chloride.

The compound of the formula (IIf) may also be present as anotherenantiomer, racemate or, if possible, in meso form or as an isomermixture.

A further embodiment of the process according to the invention relatesto the preparation of the compound of the formula (I) via nitrilecompounds of the formula (IV), as shown in scheme 3.

The compound of the formula (IVa)

-   -   in which the R¹, R² radicals are each as defined above,        can be obtained by addition of a compound of the formula (III)

-   -   in which R¹ and R² are each as defined for the compound of the        formula (IVa) and Y represents various metals such as alkali        metals or metal halide, metal alkoxide or metal carboxylate, in        which the metal may be Mg, Al, B, Mn, Cu, Cd, Zn and Sn,        onto a chiral compound of the formula (IIg)

the invention not being restricted to the stereochemical forms of thecompounds of the formula (IIg) and (IVa) shown, but rather thesecompounds may also be present as another enantiomer, racemate or, for(IIg), also in meso form or as an isomer mixture.

The chiral compound of the formula (IIg) can be obtained by thefollowing steps:

a) alkylation of the deprotonated isovaleronitrile of the formula (Xa)

with a compound of the formula (XI)

-   -   in which    -   L is a customary leaving group, such as halogen, preferably Cl        or Br, or mesylate, tosylate or triflate, etc.,        b) separation of the resulting diastereomeric nitrile and        subsequent enantiomer separation of the racemic nitrile.

The compound of the formula (IIg) may also be present as anotherenantiomer, racemate or in meso form, or a mixture thereof.

The alkylation of the isovaleronitrile can be carried out in aproticsolvents, preferably THF, toluene or ether, after an initialdeprotonation of the compound (Xa) with a strong base, such as alkalimetal hydrides or alkali metal amides, preferably lithium dialkylamidessuch as LDA or LHMDS, at from −78° C. to 0° C. or even at RT. Thedeprotonated nitrile (Xa) is then treated with 0.5 equivalent of thecompound of the formula (XI) at from −78° C. to RT, preferably at 0° C.The untreated mixture comprises an essentially equimolar mixture of thetwo possible diastereomers, which are subsequently separated.

A further preferred variant of the process according to the inventionfor preparing the compound of the formula (I) in which

R¹ is 1-methoxy-3-propoxy,

R² is methoxy and

R³ is COOR⁶ in which R⁶ is H or M, in which M is an alkali metal, anequivalent of an alkaline earth metal or unbranched or branched loweralkyl having from 1 to 5 carbon atoms, benzyl or trialkylsilyl, is shownin scheme 4.

The compound of the formula (I) is obtainable by alkylating the phenolicgroup of a compound of the formula (Ia)

-   -   in which C(O)X is as defined above for R³        with 3-methoxy-1-propyl halide, preferably chloride or bromide,        in the presence of a base.

The compounds of the formula (Ia) can be prepared according to scheme 3by Friedel-Crafts reaction of a compound of the formula (IIe) or (IIf)in which W is halogen, preferably Cl or Br, or OCOR¹² in which R¹² isbranched lower alkyl having from 1 to 5 carbon atoms, preferablypivaloyl, or OCOCF₃, OSO₂CH₃ or OSO₂CF₃, and R¹³ is branched orunbranched lower alkyl having from 1 to 5 carbon atoms or is benzyl,

with a compound of the formula (IIIb)

-   -   in which PRG is a protecting group such as trifluoroacetate or        trifluoromethanesulfonate,        to obtain a compound of the formula (IVb)

-   -   in which C(O)X is as defined above for R³.

The hydrolytic removal of the leaving group PRG to obtain the freehydroxyl function can alternatively be effected before or after thereduction of the 8-oxo group.

The reaction can be carried out in aprotic solvents customary forFriedel-Crafts reactions, preferably chlorinated hydrocarbons such asmethylene chloride, dichloroethane, or hydrocarbons, preferably hexaneor heptane. The Lewis acids used as the catalyst may be BF₃-etherate ormetal halides, preferably aluminum halides or triflates, zinc halides ortriflates or bismuth halides or triflates. The reaction temperature maybe between room temperature and reflux temperature of the solvent.

The 8-oxo group can be reduced by the processes described above.

EXAMPLES Example 1 trans-2,7-Diisopropyloct-4-ene-1,8-dionic acid

To a cooled (−78° C.) solution of diisopropylamine (58.7 g; 580 mmol) indry THF (300 ml) was slowly added n-BuLi (362 ml, 1.6 M in hexane).After stirring at −78° C. for 10 min, isovaleric acid (29.5 g, 290 mmol)was slowly added dropwise. On completion of addition, the reactionmixture was warmed to 0° C. over the course of 1 h, andtrans-1,4-dichloro-2-butene (17.3 g, 138 mmol) was added slowly at 0° C.On completion of addition, the reaction mixture was stirred at RT for 16h. The reaction mixture was then added to water (400 ml). The waterlayer was extracted 3× with t-butyl methyl ether, and the aqueous phasewas subsequently acidified with concentrated HCl. The acidic water layerwas extracted 3× with t-butyl methyl ether, dried over MgSO₄ andconcentrated under reduced pressure to obtaintrans-2,7-diisopropyloct-4-enedionic acid as a white powder (36 g;meso/rac: 53:47; purity (HPLC): 95%). Recrystallization frommethylcyclohexane gave trans-2,7-diisopropyloct-4-enedionic acid (28.3g; 80%) as white crystals.

¹H NMR (CDCl₃, 400 MHz): δ=0.95 (m, 12H); 1.86 (m, 2H); 2.22 (m, 6H);5.45/5.50 (2 m, 2H); 10.4 (bs, 2H).

¹³C NMR (CDCl₃, 100.6 MHz): δ=19.90; 20.51; 20.56; 30.04; 30.22; 31.88;32.32; 52.81; 52.86; 129.40; 129.44; 180.25; 180.59;

MS: (Cl, ammonia): m/z=274.2 [M+NH₄ ⁺]; 256.2 [M⁺].

Example 2 Diastereomer separation:(2R,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (IIe in whichW═OH) and (2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid and(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid

A mixture of meso and racemic trans-2,7-diisopropyloct-4-ene-1,8-dionicacid (17.7 g; meso/rac=49:51) was dissolved in hot isopropyl acetate (16g) and cooled to RT within 1 h. The spontaneously crystallizing materialwas filtered off and washed 3× with hexane (10 g) to obtainrac-trans-2,7-diisopropyloct-4-enedionic acid (3.8 g; meso/rac=4:96).Recrystallization of this material from isopropyl acetate gave pureracemic diacid (IIe) (purity>99%). Acetone (20 g) was added to themother solution and the mixture was stirred for 30 min. The crystalswere filtered off and washed with acetone to obtain the meso-diacid(IIe) (3.3 g, meso/rac=87:13). Evaporating off the mother solution gavea mixture of meso and racemic diacid (10.3 g, meso/rac=59:41), which wasused again for the separation.

meso: (2R,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid, meltingpoint: 108° C.

¹H NMR (CDCl₃, 400 MHz): δ=0.95 (m, 12H); 1.86 (m, 2H); 2.22 (m, 6H);5.55 (m, 2H); 9.9 (bs, 2H).

¹³C NMR (CDCl₃, 100.6 MHz): δ=19.90; 20.51; 30.04; 31.88; 52.81; 129.43;180.26.

rac-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid, melting point:108.5° C.

¹H NMR (CDCl₃, 400 MHz): δ=0.95 (m, 12H); 1.86 (m, 2H); 2.22 (m, 6H);5.45 (m, 2H); 10.4 (bs, 2H).

¹³C NMR (CDCl₃, 100.6 MHz): δ=20.04; 20.72; 30.41; 32.45; 52.99; 129.58;180.50.

Example 3 Enantiomer separation of the racemic mixture:(2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid and(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid

3a) Enantiomer Separation with (+)-ephedrine

To a solution of racemic trans-2,7-diisopropyloct-4-ene-1,8-dionic acid(10 g, 39 mmol) in acetone (80 ml) was added (+)-ephedrine (10.2 g, 61.7mmol). After the mixture had been stirred at RT for 1 h, the crystalswere filtered off and washed with hexane to obtain(+)-ephedrine*(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acidwith a diastereomer ratio of 82:18 (HPLC). Recrystallization fromacetone gave 4.9 g of the(+)-ephedrine*(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acidwith a diastereomer ratio of 98:2 (HPLC).

The other enantiomer, the(+)-(2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid, can beisolated from the mother solution.

Salt splitting: The(+)-ephedrine*(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid(4.9 g) was treated with tert-butyl methyl ether and aqueous 1N NaOH.The water layer was extracted 3× with tert-butyl methyl ether and thenacidified with concentrated HCl. The acidic water layer was extracted 3×with t-butyl methyl ether, dried over MgSO₄ and concentrated underreduced pressure to obtain(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (2.2 g, 8.4mmol) as a colorless solid which crystallized slowly.

(−)-(2S,7S)-trans-2,7-Diisopropyloct-4-ene-1,8-dionic acid,[α]_(D)=−12.3 (c=1; acetone)

The determination of the absolute configuration was determined by meansof X-ray structural analysis of crystals of the salt of(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid withS-1-(4-methylphenyl)ethylamine.

3b) Enantiomer Separation with L-phenylalaminol

To a solution of racemic trans-2,7-diisopropyloct-4-ene-1,8-dionic acid(0.5 g, 2 mmol) in acetone (4 ml) was added L-phenylalaminol (0.46 g, 3mmol). After the mixture had been stirred at RT for 1.5 h, the crystalswere filtered off and washed with hexane to obtain 0.41 g (0.73 mmol) ofL-phenylalaminol*(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionicacid. Recrystallization from acetone gave 0.24 g (0.42 mmol) ofL-phenylalaminol*(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionicacid with a diastereomer ratio of 98:2 (HPLC).

The other enantiomer, the(+)-(2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid, can beisolated from the mother solution.

Salt splitting: TheL-phenylalaminol*(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionicacid (0.24 g) was treated with tert-butyl methyl ether and aqueous 1NNaOH. The water layer was extracted 3× with tert-butyl methyl ether,then acidified with concentrated HCl and extracted another 3× withtert-butyl methyl ether. The organic layer of the acidic extraction wasdried over MgSO₄ and concentrated under reduced pressure to obtain(−)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (0.10 g, 0.39mmol) as a colorless solid which crystallized slowly.

Example 4 Isomerization ofmeso-(2R,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid and/or(2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid

Meso-(2R,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (1 g, 3.9mmol) was dissolved in acetic anhydride (10 ml), and potassium acetate(40 mg, 0.4 mmol) was added. The mixture was heated under reflux for 36h and the reaction mixture was added to water. The aqueous layer wasextracted 3× with tert-butyl methyl ether and the organic layer wasconcentrated under reduced pressure. The residue was dissolved inaqueous 1N NaOH and stirred for 2 h. The solution was acidified with HCland the aqueous layer was extracted 3× with tert-butyl methyl ether. Theorganic layer was dried over MgSO₄ and concentrated under reducedpressure to obtain trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (1 g,3.9 mmol, HPLC: meso/rac=1:1) as a yellow solid.

Analogously to this process,(2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid or mixtures of(2R,7S) and (2R,7R)dionic acid were isomerized.

Example 5 (2S,7S)-trans-2,7-Diisopropyloct-4-ene-1,8-dionyl chloride(IIe with W═Cl)

To a solution of (2S,7S)-trans-2,7-diisopropyloct-4-enedionic acid (2.0g; 7.8 mmol) in dichloromethane (20 ml) was added oxalyl chloride (2.7ml; 31.5 mmol), and the solution was stirred at RT for 16 h. Thesolution was concentrated under reduced pressure, evaporated off 2× withmethylcyclohexane and dried under reduced pressure to obtain(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionyl chloride as acolorless oil (2.3 g; 7.8 mmol), which was used without purification inthe next stage.

Example 6(2S,7S)-trans-2-Isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-8-methyl-non-4-enoicacid (IV with R¹=3-methoxypropoxy and R²=methoxy and X═OH)

To a cooled (−78° C.) solution of4-bromo-1-methoxy-2-(3-methoxypropyloxy)-benzene (III withR¹=1-methoxy-3-propoxy and R²=methoxy and Y═Br) (2.4 g; 8.5 mmol) in dryTHF (7 ml) was added dropwise n-BuLi (5.9 ml; 1.6 M in hexane), and thereaction mixture was stirred at −78° C. for 30 min. Thereafter, an MgCl₂solution (20.1 ml; 0.505 M in THF) was added, and the reaction mixturewas stirred at −78° C. for 20 min, warmed to RT and stirred for afurther 30 min. This reaction mixture was added slowly to a cooledsuspension of (2S,7S)-trans-2,7-diisopropyloct-4-enedionyl chloride (2.3g; 7.8 mmol) and CuI (148 mg, 0.78 mmol) in dry THF (9 ml). The reactionmixture was stirred at −78° C. for 20 min, warmed to RT and stirred fora further 45 min. After adding water (40 ml), the reaction mixture wasstirred for 1 h and then acidified with HCl. The aqueous layer wasextracted 3× with tert-butyl methyl ether and the organic layer wasdried over MgSO₄ and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (eluent: hexane,tert-butyl methyl ether 3:1+0.5% acetic acid) to obtain the titlecompound (IV) (1.5 g; 3.45 mmol; 44% yield) as a pale yellow oil.(2S,7S)-trans-2,7-Diisopropyloct-4-enedionic acid (0.4 g; 1.6 mmol; 20%)was likewise isolated and used once again in a repeat step.

(2S,7S)-trans-2-Isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-8-methyl-non-4-enoicacid (IV with R¹=3-methoxypropoxy and R²=methoxy and X═OH) TLC:(hexane:t-BME 1:1+0.5% acetic acid): Rf=0.3;

¹H NMR (CDCl₃, 400 MHz): δ=0.90 (m, 12H); 1.81 (m, 1H); 1.98-2.29 (m,7H); 2.45 (m, 1H); 3.21 (m, 1H); 3.38 (s, 3H); 3.59 (dd, J₁=J₂=7 Hz,2H); 3.92 (s, 3H); 4.18 (dd, J₁=J₂=7 Hz, 2H); 5.38 (m, 2H); 6.89 (d, J=9Hz, 1H); 7.54 (m, 2H); 7.75 (bs, 1H).

¹³C NMR (CDCl₃, 100.6 MHz): δ=19.68; 19.75; 20.02; 21.19; 29.39; 29.56;29.69; 30.49; 32.20; 32.39; 52.30; 56.01; 58.54; 66.18; 69.26; 110.46;112.50; 122.67; 128.92; 130.10; 131.67; 148.48; 153.57; 179.60; 202.64.

Example 7(2S,7R)-trans-2-Isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyl-non-4-enoicacid (I with R¹=3-methoxypropoxy and R²=methoxy and X═OH)

To a solution of(2S,7S)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzoyl]-8-methylnon-4-enoicacid (1.4 g; 3.2 mmol) in 1,2-dichloroethane were added triethylsilane(3.7 g; 32 mmol) and boron trifluoride diethyl etherate (2.7 g; 19.2mmol), and the solution was stirred at 33° C. for 3 days. The reactionmixture was added to water and the aqueous layer was extracted 3× withtert-butyl methyl ether. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The remaining residue was purifiedby flash chromatography (silica gel; hexane/acetone 4:1) to obtain(2S,7R)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnon-4-enoicacid (0.97 g, 2.3 mmol, 72% yield). The NMR data are identical to thedata described in US2003/0149303 A1.

Example 8(2S,7S)-trans-2-Isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-8-methyl-non-4-enoicacid (IV with R¹=3-methoxypropoxy and R²=methoxy and X═OH)

To a cooled (−78° C.) solution of4-bromo-1-methoxy-2-(3-methoxypropyloxy)-benzene (III withR¹=1-methoxy-3-propoxy and R²=methoxy and Y═Br) (1.1 g; 3.9 mmol) in dryTHF (6 ml) was added dropwise n-BuLi (2.8 ml; 1.6 M in hexane), and thereaction mixture was stirred at −78° C. for 45 min. This reactionmixture was added slowly to a cooled (−78° C.) suspension of(2S,7S)-trans-2,7-diisopropyloct-4-enedionyl chloride (1.0 g; 3.4 mmol)and CuI (65 mg, 0.34 mmol) in dry THF (4 ml). The reaction mixture wasstirred at −78° C. for 45 min, warmed to RT and stirred for a further 2h. After addition of water (20 ml), the reaction mixture was stirred for1 h and then acidified with HCl. The aqueous layer was extracted 3× withtert-butyl methyl ether and the organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The crude residue was purified byflash chromatography (hexane, tert-butyl methyl ether 3:1+0.5% aceticacid) to obtain the title compound (IV) (0.296 g; 0.68 mmol; 20% yield)as a pale yellow oil. (2S,7S)-trans-2,7-Diisopropyloct-4-enedionic acid(0.21 g; 0.82 mmol; 24% yield) was likewise isolated and reused.

Example 9(2S,7R)-trans-2-Isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyl-non-4-enoicacid (I with R¹=3-methoxypropoxy and R²=methoxy and X═OH)

To a solution of(2S,7S)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropyloxy)-benzoyl]-8-methylnon-4-enoicacid (90 mg; 0.21 mmol) in trifluoroacetic acid (1 ml) was addedtriethylsilane (250 μl; 1.5 mmol). After stirring the solution at RT for1 day, a second portion of triethylsilane (250 μl; 1.5 mmol) was added,and the solution was stirred at RT for a further 2 days and then addedto water. The aqueous layer was extracted 3× with tert-butyl methylether and the organic layer was dried over MgSO₄ and concentrated underreduced pressure. The crude residue was purified by flash chromatography(silica gel; hexane/acetone 4:1) to obtain(2S,7R)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnon-4-enoicacid (53 mg, 0.126 mmol, 61% yield).

Example 10

rac-(2S,7S)-trans-2,7-Diisopropyloct-4-ene-1,8-dionic acid dimethylester (IIe with W═OMe):

To a mixture of rac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionicacid (5.13 g; 20 mmol) in dichloromethane (55 ml) was added oxalylchloride (7.62 g; 60 mmol), and the mixture was stirred at roomtemperature for 20 h. Methanol (3.2 g; 100 mmol) was then added slowlyand the mixture was stirred at RT for 3 h. The reaction mixture wasconcentrated under reduced pressure. Water (30 ml) was added to theresidue and the mixture was extracted with tert-butyl methyl ether(TBME) (3*30 ml). The organic phase was washed with 5% aqueous NaOHsolution (5 ml), dried over MgSO₄ and concentrated under reducedpressure. rac-(2S,7S)-trans-2,7-Diisopropyloct-4-ene-1,8-dionic aciddimethyl ester was obtained as a colorless oil (5.58 g, 98% of theory).

¹H NMR (CDCl₃, 400 MHz): δ=0.85-0.95 (m, 12H); 1.84 (m, 2H); 2.12-2.29(m, 6H); 3.65 (s, 6H); 5.38 (m, 2H).

¹³C NMR (CDCl₃, 100.6 MHz): δ=20.27, 20.43; 30.19; 32.78, 51.08; 52.79;129.36; 175.46.

Example 11 rac-(2S,7S)-trans-2,7-Diisopropyloct-4-ene-1,8-dionic acidmonomethyl ester (IIf with R¹³=Me; W═OH)

To a solution of rac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionicacid dimethyl ester (1.85 g; 6.5 mmol) in methanol (10 ml) was addedsodium hydroxide (0.286 mg; 7.15 mmol) in water (1.5 ml), and themixture was stirred at 60° C. for 4 h. Subsequently, the mixture wascooled to room temperature and stirred for a further 16 h. The reactionmixture was then diluted with water (40 ml) and subsequently extractedwith TBME (3×15 ml). The organic phase was dried over MgSO₄ andconcentrated under reduced pressure, and unreacted starting materialrac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid dimethylester (0.72 mg; 2.5 mmol) was removed and can be reused. The aqueousphase was acidified with 4N hydrochloric acid and extracted with TBME(3×15 ml). The organic phase of this acidic extraction was dried overMgSO₄ and concentrated under reduced pressure. A colorless oil wasobtained (1.10 g). Purification by means of column chromatography(silica gel, pentane/isopropyl acetate 4:1) affordedrac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid monomethylester (0.74 g; 2.74 mmol; 42% of theory; 70% based on the conversion).Additionally obtained was alsorac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (0.16 g; 0.62mmol; 10%), which can be reused, for example, in the synthesis accordingto example 10.

¹H NMR (CDCl₃, 400 MHz): δ=0.88-0.97 (m, 12H); 1.85 (m, 2H); 2.12-2.31(m, 6H); 3.66 (s, 3H); 5.43 (m, 2H).

¹³C NMR (CDCl₃, 100.6 MHz): δ=20.11; 20.17; 20.26; 20.32; 29.93; 30.20;32.33; 32.82; 51.16; 52.48; 52.54; 52.83; 129.13; 129.64; 175.63;180.71.

Example 12 Acid chloride ofrac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid monomethylester (IIf with R¹³=Me; W═Cl)

To a solution of rac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionicacid monomethyl ester (0.74 g; 2.74 mmol) in dichloromethane (10 ml) wasadded oxalyl chloride (522 mg; 4.11 mmol), and the mixture was stirredat RT for 16 h. The mixture was concentrated under reduced pressure andcoevaporated twice with methylcyclohexane. This afforded the acidchloride of rac-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acidmonomethyl ester (0.79 g; quant.) as a colorless oil, which can be usedfurther without purification.

Example 13trans-2-Isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-8-methylnon-4-enoicacid methyl ester (IV with R¹³=Me according to scheme 2)

To a cooled (−78° C.) solution of4-bromo-1-methoxy-2-(3-methoxypropyloxy)-benzene (8.25 g; 30 mmol) indry tetrahydrofuran (THF) (25 ml) was added dropwise n-BuLi (20 ml; 1.6M in hexane), and the reaction mixture was stirred at −78° C. for 30min. A freshly prepared solution of MgCl₂ (90 ml; 0.505 M in THF) wasthen added slowly and the mixture was stirred at −78° C. for 30 min. Themixture was warmed to room temperature with stirring within 30 min andstirred for a further 30 min. This reaction mixture was then addedslowly to a cooled (−78° C.) suspension of the acid chloride oftrans-2,7-diisopropyloct-4-ene-1,8-dionic acid monomethyl ester (8.33 g;28.8 mmol) and CuI (560 mg, 2.9 mmol) in dry tetrahydrofuran (40 ml).The reaction mixture was stirred at −78° C. for 40 min, warmed to RT andstirred for a further 16 h. After adding water (200 ml), the reactionmixture was stirred for 1 h and then acidified with HCl. The aqueousphase was extracted with tert-butyl methyl ether (5×100 ml), and theorganic phase was washed with 5% aqueous sodium hydroxide solution (50ml) and then with saturated sodium chloride solution (50 ml), dried overMgSO₄ and concentrated under reduced pressure. The crude residue (12 g)was purified by flash chromatography (pentane/acetone 8:1) to obtaintrans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-8-methylnon-4-enoicacid (1.55 g; 3.5 mmol, 12%) as a pale yellow oil.

¹H NMR (CDCl₃, 400 MHz): δ=0.80-0.95 (m, 12H); 1.75 (m, 1H); 1.90-2.30(m, 7H); 2.45 (m, 1H); 3.22 (m, 1H); 3.37 (s, 3H); 3.57 (dd, 2H); 3.64(s, 3H); 3.93 (s, 3H); 4.19 (dd, J1=J2=7 Hz, 2H); 5.35 (m, 2H); 6.88 (d,J=9 Hz, 1H); 7.54 (m, 2H).

The invention claimed is:
 1. A process for preparing compounds of thegeneral formula (I)

in which R¹ and R² are each independently hydroxyl, alkoxy, aryloxy,arylalkyloxy or alkoxyalkoxy, the latter four groups each beingunsubstituted or substituted; R³ is a heterocarbon group containing atleast one heteroatom selected from O and N with at least onecarbon-heteroatom multiple bond at the C-1 position, said group beingbonded via the C-1 atom and being selected from COOR⁶, in which R⁶ ishydrogen, alkyl, aryl, arylalkyl or trialkylsilyl, wherein the alkyl andthe aryl may each be unsubstituted or substituted; nitrile; C(O)R⁷, inwhich R⁷ is selected from hydrogen, halogen, O⁻, OM, in which M is analkali metal or an equivalent of an alkaline earth metal, OCOR¹², inwhich R¹² is unsubstituted or substituted branched lower alkyl havingfrom 1 to 5 carbon atoms, or pivaloyl, OCOCF₃, OSO₂CH₃ or OSO₂CF₃; or R³comprises a protecting or activating group customary for carboxylicacids, or is C(O)NR⁴R⁵, in which R⁴ and R⁵ are independently hydrogen,alkyl, aryl, arylalkyl, or trialkylsilyl, wherein the alkyl and the arylmay each be unsubstituted or substituted, or R⁴ and R⁵ together with thenitrogen form a five- to six-membered heterocyclic ring system which mayoptionally have from 1 to 3 additional heteroatoms; or salts thereof,wherein a compound of the general formula (II)

in which R³ is in each case independently as defined above under theformula (I); is reacted in an addition reaction with a compound of theformula (III)

in which Y is halogen, metal, metal halide, metal alkoxide or metalcarboxylate, R¹ and R² are each as defined above under the formula (I),to obtain a compound of the formula (IV)

in which R¹, R² and R³ are each as defined above under the formula (I);the dotted line represents a single or double bond; R⁵ is O or NR⁸ inwhich R⁸ is hydrogen or unsubstituted or substituted alkyl if the dottedline represents a double bond, or R⁵ is OH or NR⁸R⁹ in which R⁸ and R⁹are each independently hydrogen, alkyl or aryl or alkylaryl, each beingunsubstituted or substituted if the dotted line represents a singlebond; and the compound of the formula (IV) is subjected to at least onereduction reaction to obtain the desired product of the formula (I),wherein substituted means substituted by one or more of the followinggroups selected from halogen, hydroxyl, cyano, C₁-C₆-alkoxy, nitro,amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, carboxyl,C₁-C₆-alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl,trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl, andpentahaloelhyl.
 2. The process of claim 1, in which the compound of theformula (II) is used as a mixture of the isomers.
 3. The process ofclaim 1, comprising an additional isomer separation step before or afterone of the addition or reduction steps and optionally additionally anisomerization or racemization of the undesired isomers.
 4. The processas claimed in claim 1, in which the radicals in the formula (I) are eachdefined as follows: R¹: hydroxyl or unsubstituted or substitutedbranched or unbranched lower alkoxy having from 1 to 5 carbon atoms,unsubstituted or substituted aryloxy or unsubstituted or substitutedbranched or unbranched alkoxyalkoxy having in each case from 1 to 5carbon atoms in the alkoxy group, R²: hydroxyl or unsubstituted orsubstituted branched or unbranched lower alkoxy having from 1 to 5carbon atoms, unsubstituted or substituted aryloxy or unsubstituted orsubstituted branched or unbranched alkoxyalkoxy having in each case from1 to 5 carbon atoms in the alkoxy group, and R³: COOR⁶ in which R⁶ ishydrogen, branched or unbranched lower alkyl having from 1 to 5 carbonatoms, aryl, benzyl or trialkylsilyl, wherein the alkyl and the aryl mayeach be unsubstituted or substituted, nitrile, C(O)R⁷ in which R⁷ ishydrogen, halogen, O⁻, OM in which M is an alkali metal or an equivalentof an alkaline earth metal, or C(O)NR⁴R⁵ in which R⁴ and R⁵ areindependently unsubstituted or substituted branched or unbranched loweralkyl having from 1 to 5 carbon atoms, or benzyl.
 5. The process ofclaim 3, in which the compound of the formula (I) corresponds to theformula (VI)

in which R¹, R² and R³ are each as defined above under formula (I). 6.The process of claim 5, in which the compound of the formula (I)corresponds to the formula (VII)

in which MOPO is methoxypropoxy and R⁶ is as defined above under formula(I).
 7. The process as claimed in claim 1, in which R³ is independentlyCOOR⁶, in which R⁶ is hydrogen, alkyl, aryl, arylalkyl or trialkylsilyl,wherein the alkyl and the aryl may each be unsubstituted or substituted;nitrile; C(O)R⁷, in which R⁷ is halogen, O⁻, OM, in which M is an alkalimetal or an equivalent of an alkaline earth metal.
 8. The process asclaimed in claim 1, in which the addition reaction is carried out with acompound of the formula (III) in which Y is Li, Na, CuCl, CuBr, CuI,MgCl or MgBr.
 9. The process as claimed in claim 1, in which thereduction is carried out in one or two steps with metal hydride ortrialkylsilane in the presence of acids or with Lewis acids.
 10. Theprocess of claim 6, in which the compound of the formula (VII) isconverted in an additional amidation to the compound of the formula(VIII)


11. Compounds of the formula (IV)

in which R¹ and R² are each independently hydroxyl, alkoxy, aryloxy,arylalkyloxy or alkoxyalkoxy, the latter four groups each beingunsubstituted or substituted; R³ is a heterocarbon group containing atleast one heteroatom selected from O and N with at least onecarbon-heteroatom multiple bond at the C-1 position, said group beingbonded via the C-1 atom and being selected from COOR⁶, in which R⁶ ishydrogen, alkyl, aryl, arylalkyl or trialkylsilyl, wherein the alkyl andthe aryl may each be unsubstituted or substituted; nitrile; C(O)R⁷, inwhich R⁷ is selected from hydrogen, halogen, O⁻, OM, in which M is analkali metal or an equivalent of an alkaline earth metal, OCOR¹², inwhich R¹² is unsubstituted or substituted branched lower alkyl havingfrom 1 to 5 carbon atoms, or pivaloyl, OCOCF₃, OSO₂CH₃ or OSO₂CF₃; or R³comprises a protecting or activating group customary for carboxylicacids, or is C(O)NR⁴R⁵, in which R⁴ and R⁵ are independently hydrogen,alkyl, aryl, arylalkyl, or trialkylsilyl, wherein the alkyl and the arylmay each be unsubstituted or substituted, or R⁴ and R⁵ together with thenitrogen form a five- to six-membered heterocyclic ring system which mayoptionally have from 1 to 3 additional heteroatoms; or salts thereof;the dotted line represents a single or double bond; R⁵ is O or NR⁸ inwhich R⁸ is hydrogen or unsubstituted or substituted alkyl if the dottedline represents a double bond, or R⁵ is OH or NH₂ if the dotted linerepresents a single bond, or salts thereof, wherein substituted meanssubstituted by one or more of the following groups selected fromhalogen, hydroxyl, cyano, C₁-C₆-alkoxy, nitro, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino, carboxyl, C₁-C₆-alkoxycarbonyl, aminocarbonyl,halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl,trihaloethyl, tetrahaloethyl, and penlahaloethyl.
 12. The compounds ofthe formula (IV)

in which R¹ and R² are each independently hydroxyl, alkoxy, aryloxy,arylalkyloxy or alkoxyalkoxy, the latter four groups each beingunsubstituted or substituted; R³ is a heterocarbon group containing atleast one heteroatom selected from O and N with at least onecarbon-heteroatom multiple bond at the C-1 position, said group beingbonded via the C-1 atom and being selected from COOR⁶, in which R⁶ ishydrogen, alkyl, aryl, arylalkyl or trialkylsilyl, wherein the alkyl andthe aryl may each be unsubstituted or substituted; nitrile; C(O)R⁷, inwhich R⁷ is selected from hydrogen, halogen, O⁻, OM, in which M is analkali metal or an equivalent of an alkaline earth metal, OCOR¹², inwhich R¹² is unsubstituted or substituted branched lower alkyl havingfrom 1 to 5 carbon atoms, or pivaloyl, OCOCF₃, OSO₂CH₃ or OSO₂CF₃; or R³comprises a protecting or activating group customary for carboxylicacids, or is C(O)NR⁴R⁵, in which R⁴ and R⁵ are independently hydrogen,alkyl, aryl, arylalkyl, or trialkylsilyl, wherein the alkyl and the arylmay each be unsubstituted or substituted, or R⁴ and R⁵ together with thenitrogen form a five- to six-membered heterocyclic ring system which mayoptionally have from 1 to 3 additional heteroatoms; or salts thereof;the dotted line represents a single or double bond; R⁵ is O or NR⁸ inwhich R⁸ is hydrogen or unsubstituted or substituted alkyl if the dottedline represents a double bond, or R⁵ is OH or NH, if the dotted linerepresents a single bond, or salts thereof, as the (S,S)-enantiomers,wherein substituted means substituted by one or more of the followinggroups selected from halogen, hydroxyl, cyano, C₁-C₆-alkoxy, nitro,amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, carboxyl,C₁-C₆-alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl,trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl,penlahaloethyl.
 13. The process as claimed in claim 1 for preparingcompounds of the general formula (I)

in which R¹ and R² are each independently hydroxyl, alkoxy, aryloxy,arylalkyloxy or alkoxyalkoxy, the latter four groups each beingunsubstituted or substituted; R³ is COOR⁶ in which R⁶ is hydrogen,alkyl, aryl, arylalkyl or trialkylsilyl, wherein the alkyl and the arylmay be unsubstituted or substituted; nitrile; C(O)R⁷, in which R⁷ isselected from halogen O⁻, OM, in which M is an alkali metal or anequivalent of an alkaline earth metal, OCOR¹² in which R¹² isunsubstituted or substituted branched lower alkyl having from 1 to 5carbon atoms, or pivaloyl, OSO₂CH₃ or OSO₂CF₃; or salts thereof, whereina compound of the general formula (II)

in which R³ is in each case independently as defined above under theformula (I); is reacted in an addition reaction with a compound of theformula (III)

in which Y is halogen, metal, metal halide, metal alkoxide or metalcarboxylate, preferably Li, Na, Mg, Zn, Cu and B, R¹ and R² are each asdefined above under the formula (I), to obtain a compound of the formula(IV)

in which R¹ and R² are each independently hydroxyl, alkoxy, aryloxy,arylalkyloxy or alkoxyalkoxy, the latter four groups each beingunsubstituted or substituted; R³ is a heterocarbon group containing atleast one heteroatom selected from O and N with at least onecarbon-heteroatom multiple bond at the C-1 position, said group beingbonded via the C-1 atom and being selected from COOR⁶, in which R⁶ ishydrogen, alkyl, aryl, arylalkyl or trialkylsilyl, wherein the alkyl andthe aryl may each be unsubstituted or substituted; nitrile; C(O)R⁷, inwhich R⁷ is selected from hydrogen, halogen, O⁻, OM, in which M is analkali metal or an equivalent of an alkaline earth metal, OCOR¹², inwhich R¹² is unsubstituted or substituted branched lower alkyl havingfrom 1 to 5 carbon atoms, or pivaloyl, OCOCF₃, OSO₂CH₃ or OSO₂CF₃; or R³comprises a protecting or activating group customary for carboxylicacids, or is C(O)NR⁴R⁵, in which R⁴ and R⁵ are independently hydrogen,alkyl, aryl, arylalkyl, or trialkylsilyl, wherein the alkyl and the arylmay each be unsubstituted or substituted, or R⁴ and R⁵ together with thenitrogen form a five- to six-membered heterocyclic ring system which mayoptionally have from 1 to 3 additional heteroatoms; or salts thereof;the dotted line represents a double bond; R⁵ is O; and the compound ofthe formula (IV) is subjected to at least one reduction reaction toobtain the desired product of the formula (I).
 14. The process asclaimed in claim 1, wherein the protecting or activating group customaryfor carboxylic acids is selected form C(O)N-alkyl-O-alkyl.
 15. Theprocess as claimed in claim 4, in which the radicals R¹ and R² in theformula (I) are each defined as follows: R¹: hydroxyl or unsubstitutedor substituted methoxy, ethoxy, n- and i-propoxy, n-, i- and t-butoxy orpentoxy, unsubstituted or substituted phenyloxy, naphthyloxy orderivatives thereof, or benzyloxy or unsubstituted or substituted1-methoxymethoxy, 1-methoxy-2-ethoxy, 1-methoxy-3-propoxy,1-methoxy-4-butoxy, and R²: hydroxyl or unsubstituted or substitutedmethoxy, ethoxy, n- and i-propoxy, n-, i- and t-butoxy or pentoxy,unsubstituted or substituted phenyloxy, naphthyloxy or derivativesthereof, or benzyloxy or unsubstituted or substituted 1-methoxymethoxy,1-methoxy-2-ethoxy, 1-methoxy-3-propoxy, 1-methoxy-4-butoxy.
 16. Theprocess as claimed in claim 1, in which R⁶ in Group COOR⁶ is hydrogen.